Increased secretion of amylin by pancreatic beta-cells (hyperamylinemia) is common in obese and insulin resistant patients, coincides with hyperinsulinemia, and promotes formation of toxic amylin oligomers. Oligomeric amylin induces beta-cell apoptosis contributing to the development of type-2 diabetes. Recent studies demonstrate that amylin oligomers also affect the vascular system, kidneys, and heart. Our data show large deposits of oligomerized amylin in failing hearts from obese and T2D patients, but not in hearts from controls. Oligomeric amylin was found in myocyte injury areas suggesting a role in the mechanism of injury. Indeed, our pilot study on a humanized rat model of hyperamylinemia (the HIP rat) indicates that amylin oligomers attach to cardiac myocytes and induce oxidative stress and Ca2+ dysregulation leading to diastolic dysfunction and hypertrophy. The pilot study also suggests that endogenous molecules with anti-aggregation properties, such as plasmin and epoxyeicosanoids, limit cardiac accumulation of amylin and its myopathic response. Based on these preliminary results, our research proposal will test the hypotheses that 1) cardiac accumulation of oligomerized amylin accelerates diabetic heart injury by inducing sarcolemmal damage and oxidative stress, and 2) limiting amylin deposition in the heart may reduce/ delay the onset of diabetic heart failure. These hypotheses will mechanistically be assessed by using transgenic rat models overexpressing either the amyloido- genic human amylin (HIP rats) or the non-amyloidogenic rat amylin isoform (UCD rats). Specifically, planned studies will determine how accumulation of oligomerized amylin in the HIP rat heart a) disrupts sarcolemmal processes, b) induces oxidative stress and myocyte Ca2+ dysregulation, and c) activates Ca2+-mediated CaMKII-HDAC and calcineurin-NFAT hypertrophy signaling pathways. Based on the results of our pilot study, cardiac dysfunction in HIP rats is expected to develop even in pre-diabetes, as often observed in humans. In contrast, our pilot study predicts that UCD rats matched for age and glucose, but lacking cardiac amylin deposition, may show signs of cardiac dysfunction after the onset of diabetes. Our research will also determine if disrupting deposition of oligomeric amylin in the heart and recovering sarcolemmal integrity improve cardiac function in the HIP rat model. This innovative concept will be explored in longitudinal studies using membrane sealants and scavengers of circulating amylin oligomers. Hence, our research project proposes that amylin buildup is a key contributor to the multifactorial pathogenesis of diabetic heart injury and that mitigating amylin oligomer accumulation could delay the onset of diabetic heart failure. If our hypothesis of cardiotoxic amylin oligomer is proven, then circulating amylin oligomers are a feasible therapeutic target to reduce diabetic heart injury.